The excitatory neurotransmitter, glutamate, in the CNS is an important mediator of opioid nociception, dependence, and withdrawal (Guo Y, Wang, et al., Neurosci. Biobehav. Rev., 2009, 33(6):864-873). Glutamate exerts its effect via two different classes of glutamate receptors, ionotropic and metabotropic. Among the metabotropic receptors (mGluR), the metabotropic glutamate-5 receptor subtype (mGluR5) is widely distributed in the CNS (Patel S, et al. Nucl. Med. Biol., 2007, 34, 1009-1017), where it modulates synaptic transmission, neuronal excitability, and plasticity. The mGluR5 is a class-C G protein-coupled receptor (GPCR) whose activation is mediated by binding of glutamate to its extracellular Venus flytrap domain. It is noteworthy that the selective mGluR5 antagonist, MPEP, acts allosterically by binding to the 7TM domain of the receptor (Gasparini F, et al., Bioorg. Med. Chem. Lett., 2002, 407-409).
The low effectiveness of morphine and related mu opioid analgesics for the chronic treatment of inflammatory pain is well known. This is due to opioid-induced release of proinflammatory cytokines, which leads to increased levels of glutamate that lower the pain threshold via the mGluR5 and NMDAR. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR5) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of side effects during chronic use. Given the colocalization of opioid receptors and mGluR5 in glia and neurons, together with reports that indicate coexpressed opioid/mGluR5 receptors in cultured cells associate as heteromers, there is the possibility this could occur in vivo as well (Schröder H, et al., Neuropharmacology, 2009, 56(4), 768-778).
Morphine and many other analgesics have lower efficacy in treating pain associated with certain conditions such as cancer, serious burns, and spinal injury. Accordingly, there is currently a need for analgesic agents for treatment of pain for which current analgesics are ineffective.